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Intrinsic and Extrinsic Molecular Determinants Or Modulators For Polish Journal of Veterinary Sciences Vol. 21, No. 1 (2018), 217–227 DOI 10.24425/119040 Review Intrinsic and extrinsic molecular determinants or modulators for epigenetic remodeling and reprogramming of somatic cell-derived genome in mammalian nuclear-transferred oocytes and resultant embryos M. Samiec, M. Skrzyszowska National Research Institute of Animal Production, Department of Reproductive Biotechnology and Cryoconservation, Krakowska 1, 32-083 Balice n. Kraków, Poland Abstract The efficiency of somatic cell cloning in mammals remains disappointingly low. Incomplete and aberrant reprogramming of epigenetic memory of somatic cell nuclei in preimplantation nu- clear-transferred (NT) embryos is one of the most important factors that limit the cloning effective- ness. The extent of epigenetic genome-wide alterations, involving histone or DNA methylation and histone deacetylation, that are mediated by histone-lysine methyltransferases (HMTs) or DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be modulated/reversed via exogenous inhibitors of these enzymes throughout in vitro culture of nuclear donor cells, nuclear recipient oocytes and/or cloned embryos. The use of the artificial modifiers of epigenomically-condi- tioned gene expression leads to inhibition of both chromatin condensation and transcriptional silenc- ing the genomic DNA of somatic cells that provide a source of nuclear donors for reconstruction of enucleated oocytes and generation of cloned embryos. The onset of chromatin decondensation and gene transcriptional activity is evoked both through specific/selective inactivating HMTs by BIX-01294 and through non-specific/non-selective blocking the activity of either DNMTs by 5-aza-2’-deoxycytidine, zebularine, S-adenosylhomocysteine or HDACs by trichostatin A, valproic acid, scriptaid, oxamflatin, sodium butyrate, m-carboxycinnamic acid bishydroxamide, panobinostat, abexinostat, quisinostat, dacinostat, belinostat and psammaplin A. Epigenomic modulation of nuclear donor cells, nuclear recipient cells and/or cloned embryos may facilitate and accelerate the reprog- rammability for gene expression of donor cell nuclei that have been transplanted into a host ooplasm and subsequently underwent dedifferentiating and re-establishing the epigenetically dependent status of their transcriptional activity during pre- and postimplantation development of NT embryos. Never- theless, a comprehensive additional work is necessary to determine whether failures in the early-stage reprogramming of somatic cell-inherited genome are magnified downstream in development of cloned conceptuses and neonates. Key words: somatic cell nucleus, reconstructed oocyte, epigenomic maturity, nuclear-transferred embryo, somatic cell-inherited chromatin remodeling, donor nuclear reprogramming, epigenetic modulator/modifier Correspondence to: M. Samiec, e-mail: [email protected] 218 M. Samiec, M. Skrzyszowska Species-specific differences In the recipient cell’s cytoplasmic environment of in the reprogramming status of donor the majority of mammalian species embryos, exclud- nuclear DNA epigenomic inheritance ing sheep, heavily methylated somatic cell-inherited between mammalian somatic cell cloned genome has to undergo wide epigenetic changes, embryos which allow to erase its own methylation pattern es- tablished during cell differentiation and to restore nu- Transcriptional activity (gene expression or re- clear totipotency/pluripotency during early em- pression) of the somatic cell genome during pre- and bryogenesis. The studies aimed at examining develop- postimplantation development of cloned embryos de- ment of murine preimplantation embryos (Kishigami pends generally on the reprogramming extent of epi- et al. 2006, Esteves et al. 2011, Mason et al. 2012) genetic modifications such as demethylation/methyla- have shown not only differential (asymmetric) de- tion of nuclear DNA cytosine residues as well as methylation waves of nucleosomal histones of acetylation/deacetylation and demethylation/methyla- topologically-separated parental genomes that had tion of lysine moieties within chromatin nucleosomal been previously configured into female and male core-derived histones H3 and H4. It has been ascer- pronuclei in the fertilized eggs, but also genome-wide tained that the donor genomic DNA should undergo DNA methylation changes during preimplantation both the global and developmentally-important development. It cannot also be excluded that zygotic gene-selective demethylation processes throughout demethylation and genome-wide methylation changes the early embryogenesis of nuclear transfer-derived are not a prerequisite for normal development of oocytes to reset its own epigenetic memory estab- ovine embryos, in which a global DNA demethylation lished as a result of specific differentiation pathway of wave does not occur immediately after fertilization of somatic and germ cell lineages (Martinez-Diaz et al. ova. Despite incomplete and delayed demethylation 2010, Buganim et al. 2013, Masala et al. 2017). processes within somatic genome that had been trans- Against a background of other mammalian species ferred into the artificially activated eggs, some mam- zygotes that undergo active male pronuclear de- malian cloned embryos developed apparently nor- methylation wave, in rabbits, both the paternally- and mally (Rodriguez-Osorio et al. 2012, Anckaert and maternally-inherited genomes appear to maintain the Fair 2015, Huang et al. 2016). relatively high DNA methylation level during preim- plantation development up to the 16-cell stage. Ad- mittedly, the correlation between the frequency of nu- Influence of oocyte reconstruction technique clear DNA demethylation and advanced degree of (somatic cell nuclear transfer/SCNT method) chromatin architectural remodelling has been sugges- on the fate of the processes for architectural ted (Shi et al. 2004, Yang et al. 2007, Nashun et al. remodeling and epigenetic reprogramming 2015). Nevertheless, this dependence is presumably of donor genome in cloned embryos insufficient, because the sperm-derived genome (male pronucleus) in non-mammalian species undergoes the Nucleoplasmic (karyolymphatic) factors of a so- spatial rearrangements of chromatin nucleosomal matic cell that are engaged directly or indirectly in its conformation without active demethylation of DNA structural and functional differentiation are asso- cytosine residues. Although active (replication-inde- ciated with nuclear chromatin and their qualitative pendent) demethylation of nuclear genome seems to and quantitative composition undergoes changes to- be preserved by the embryos of different mammalian gether with progressing cytodifferentiation state species, in the rabbit embryos high DNA methylation (Campbell and Alberio 2003, Eilertsen et al. 2007, levels were found to be maintained during preimplan- Fisher and Fisher 2011). The previously-mentioned tation development (Shi et al. 2004, Corry et al. 2009, nucleoplasmic factors involve among others transcrip- Shi and Wu 2009). In contrast, Lepikhov et al. (2008) tion factors, histones, non-histone HMG (high mobil- have shown that, in rabbit nuclear-transferred em- ity group) proteins interacting with transcription- bryos at the 1-cell stage, the fibroblast cell-inherited ally-active chromatin, nuclear lamins and poly-subunit genomic DNA undergoes rapid demethylation im- protein complexes that are responsible for remodeling mediately after activation of reconstituted oocyte of spatial conformation of chromatin structures and (clonal cybrid) and formation of pseudopronucleus. for DNA topology changes. These latter include, e.g., Nonetheless, in ovine embryos derived from fertilized nucleosome remodeling factor (NURF), brahma fam- ova, a dramatic decrease in genomic DNA methyla- ily proteins (BRG1 and BRM) sharing homology with tion status was not found until the 16-blastomere related yeast factors SWI2/SNF2 (switch of mating stage will not have been reached by them (Beaujean type/sucrose non-fermenting) and multimeric epi- et al. 2004, Wen et al. 2014, Jafarpour et al. 2017). genetic modifiers, the members of which are: tran- Intrinsic and extrinsic molecular determinants... 219 scriptional activator complexes such as Trithorax dleder 2007). Moreover, reducing the volume of al- group (Trx-G) proteins and transcriptional repressor logeneic somatic cell-derived cytoplasm, which is complexes such as Polycomb group (Pc-G) proteins transplanted into the cytosolic microenvironment of (Andreu-Vieyra and Matzuk 2007, Rajasekhar and ooplast, allows to completely prevent the limitations Begemann 2007, Whitworth and Prather 2010, caused by the hybridization of heteroplasmic sources Buganim et al. 2013). When G0/G1-stage or of not only mitochondrial DNA (mtDNA) copies G2/M-stage whole donor cell is fused with enucleated (Fig. 1), but also cytoplasmic and intramitochondrial oocyte by electroporation or microinjected directly translation system-descended messenger RNAs (in- into the ooplast cytoplasm, then those specific factors cluding also polycistronic mitochondrial mRNA frac- of a somatic cell are also transferred into the cytop- tions), transporter RNAs as well as ribosomal RNAs. lasm of recipient oocyte and may block an ability of All these mtDNA or RNA fractions of heteroplasmic endogenous oocyte factors for appropriate remodel- origin are inherited both from nuclear donor somatic ing/reprogramming of both epigenetic and genomic cell and from nuclear recipient cytoplast (ooplast)
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